Neonatal Opioid Withdrawal Syndrome (NOWS) is a major public health problem, as the incidence of NOWS in the USA has increased five-fold since 2000-2012 to almost 6 per 1000 hospital births, with an increase in health care expenditures from $200 million to $1.5 billion. Current critical knowledge gaps in the field are the impact of antenatal opioid exposure and NOWS on childhood brain structure and connectivity and on medical, developmental, and behavioral trajectories in early childhood. It is also unknown how these effects are modulated by associated maternal, neonatal, and environmental factors, and how the home environment, maternal mental health, and parenting styles modify such trajectories of brain connectivity and neurodevelopment at key developmental windows. This proposal in response to the HEAL Initiative: Antenatal Opioid Exposure Longitudinal Study Consortium leverages the established infrastructure and longstanding collaborations of four of the highest enrolling clinical sites and data coordinating center of the Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN) to address these knowledge gaps. We term our proposal the Outcomes of Babies with Opioid Exposure (OBOE study). Systematic and in-depth study of a well characterized observational cohort using validated and sophisticated clinical and neuroimaging measures will improve understanding of the structural and functional sequelae resulting from prenatal opioid exposure and NOWs, and their interactions with the maternal-infant dyad. Such data will identify modifiable risk factors and suggest potentially better treatment strategies, including differences in outcomes with modification of specific environmental factors, or pharmacotherapy.